Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines

ABSTRACT

The invention relates to a process for the cis-selective preparation of cyclic amines of the sertralin type by reductive alkylation of cyclic imines or their precursors and catalytic hydrogenation in the presence of copper-containing catalysts and in the presence of a protic solvent.

This application is a continuation of application Ser. No. 10/031,882filed Jan. 25, 2002, now U.S. Pat. No. 6,720,454, which is the 371National Stage of International Application No. PCT/EP00/06932, filedJul. 20, 2000.

The invention relates to a process for the cis-selective catalytichydrogenation of cyclohexylidenamines and their precursors.

Cyclohexylamines can be used, inter alia, as antioxidants and as activeingredients in pharmaceuticals. An important cyclohexylamine issertralin:

Sertraline:(1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthylamine,cf. Merck Index Twelfth Edition 1996, No. 8612 is known as anantidepressant. The preparation of this compound is described in U.S.Pat. No. 4,536,518. The hydrochloride is commercially available, interalia, under the trade names Lustral® and Zoloft®. Cyclohexylamines ofthe type:

(R₂≠H) exist in at least two isomeric forms:

In the case of further, asymmetric substitution on the cyclohexyl ring,the carbon atoms in the 1 and 4 positions are chiral. According to theR,S nomenclature of Kahn, Ingold and Prelog, sertralin has the 1S, 4Sconfiguration.

Cyclohexylamines are obtained, for example, by the following method:reaction of the ketone:

with a primary amine, e.g. methylamine, results in elimination of waterto give a cyclohexylidenamine:

The imine formed is subsequently catalytically hydrogenated to give theamine. Such reactions proceed in only a low stereoselectivity, if any.In the case of sertralin, four enantiomers are obtained.

It is an object of the present invention to prepare cyclohexylaminescontaining a very high proportion of cis-isomers.

To achieve the object, the abovementioned U.S. Pat. No. 4,536,518, forexample, proposes hydrogenating an imine of the formula:

using palladium on carbon as support. This gives 70% of cis-racemate and30% of trans-racemate.

To improve this yield further, WO 93/01161 proposes using Raney nickelas catalyst in place of palladium on carbon as support for thehydrogenation of the imine. This gives a cis/trans ratio of 8:1.

It has now surprisingly been found that an even better cis/trans ratiois obtained when the imine is hydrogenated in the presence of acopper-containing catalyst and in the presence of a protic solvent.Although the preparation of secondary amines from ketones andintermediate imines by hydrogenation in the presence of copper chromitecatalysts is known from R. B. C. Pillai J. Mol. Catalysis 84 (1993),125-129, it is surprising that when starting from cyclohexylidenamines,which can also be formed as intermediates from ketones, thehydrogenation using a copper-containing catalyst proceedsdiastereoselectively and gives a high proportion (>95%) of cis isomers.

The invention provides a process for preparing cis compounds of theformula:

in which R₁ and R₂ are, independently of one another, hydrocarbonradicals and A are substituents and m is an integer from 0 to 4 whichdefines the number of substituents A, which comprises

a) hydrogenating a cyclohexylidenamine of the formula:

in which n is zero or 1, R₁, R₂, A and m are as defined above, in thepresence of a copper-containing catalyst and in the presence of a proticsolvent; or

b) reacting a ketone of the formula:

in which R₂, A and m are as defined above, with a compound whichintroduces the group R₁—N→(O)_(n), hydrogenating the imine or nitrone(II) obtainable as an intermediate in the presence of acopper-containing catalyst and in the presence of a protic solvent andisolating the cis compound (I).

When m is zero and the cyclohexyl ring is unsubstituted in a compound(I), the two structural formulae represent identical compounds:

In the description of the present invention, the structural formula ofthe cis compound (I) of both possibilities is represented using only theformula:

When m is from 1 to 4 (m>0) and the cyclohexyl ring is unsymmetricallysubstituted in a compound (1), the hydrogenation selectively gives a cisenantiomer pair which can be separated into the optically pureenantiomers by customary methods of racemate resolution, for example bycrystallization of the mandelic acid salt using the method of W. M.Welch et al in J. Med. Chem. 1984, 27, 1508-1515. The relationshipbetween the two cis and trans enantiomer pairs and the four opticallypure enantiomers is illustrated by the following formulae forsertraline:

In the structural formulae of the starting materials (II) and (III), theuniform-thickness bonds to the substituent R₂ indicate that in the caseof R₂≠H and different substitution on the cyclohexyl ring, thesestarting materials can be used in the process in the form of racemicmixtures having equal or different proportions of the enantiomers or inthe form of an optically pure enantiomer.

The process gives a high yield of desired cis compounds. In the case ofthe synthesis of sertralin, a ratio of the cis enantiomer pair to thetrans enantiomer pair of greater than 95:5 is obtained. In aparticularly preferred embodiment, the even better ratio of greater than99:1 is achieved. This high yield of cis compounds also eliminates theseparation of the cis enantiomer pair from the trans enantiomer pairwhich is otherwise necessary in the presence of different substituents A(m>0).

The definitions and designations used in the description of the presentinvention preferably have the following meanings:

A hydrocarbon radical R₁ or R₂ is selected, in particular, from thegroup consisting of C₁-C₂₀alkyl, C₄-C₁₂cycloalkyl,C₂-C₁₁heterocycloalkyl, carbocyclic C₅-C₁₆aryl, C₂-C₁₅heteroaryl,carbocyclic C₇-C₁₆aralkyl and C₂-C₁₅heteroarylalkyl and can additionallybe substituted by a suitable functional group, e.g. selected from thegroup of functional groups or derivatized functional groups consistingof amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, hydroxy, carboxy andhalogen.

The cyclohexyl ring can be substituted by from one to four, preferablytwo, substituents selected from the group A consisting of thesubstituents R₃, R₄, R₅ and R₆. Suitable substituents are listed in theList of Radical Names under the IUPAC Rules and remain unchanged underthe conditions of the catalytic hydrogenation reaction. The substituentsmay be chosen freely. Suitable substituents A from the group R₃, R₄, R₅and R₆ are, for example, selected from the group of functional groups orderivatized functional groups consisting of amino, C₁-C₄alkylamino,C₁-C₄dialkylamino, hydroxy, carboxy and halogen or are saturatedaliphatic, cycloaliphatic or heterocycloaliphatic radicals, carbocyclicor heterocyclic aryl radicals, fused carbocyclic, heterocyclic orcarbocyclic-heterocyclic radicals, which may in turn be combined in anyway with further radicals of this group and can be substituted by thefunctional groups or derivatized functional groups mentioned.

The abovementioned substituents and radicals can also be interrupted byone or more divalent radicals selected from the group consisting of —O—,—C(═O)—O—, —O—C(═O)—, —C(═O)—N(C₁-C₄alkyl)-, —N(C₁-C₄alkyl)-C(═O)—,—S(═O)₂—, —S(═O)₂—O—, —O—S(═O)₂—, —S(═O)₂—N(C₁-C₄alkyl)-,—(C₁-C₄alkyl)N—S(═O)₂—, —P(═O)—, —P(═O)—O—, —O—P(═O)— and —O—P(═O)—O—.

In a preferred embodiment, two substituents A from the group R₃, R₄, R₅and R₆ form divalent, bridging C₂-C₆alkylene, C₄-C₈alkyldiylidene orC₄-C₈alkenyldiylidene groups, preferably butanediylidene, in particular2-butenediylidene which is joined to the cyclohexyl ring at two adjacentcarbon atoms and together with these carbon atoms forms a phenyl ringwhich may be substitued by the abovementioned functional groups orsubstituents.

Further suitable substituents A from the group R₃, R₄, R₅ and R₆ aresubstituents selected from the group consisting of C₁-C₂₀alkyl,C₄-C₁₂cycloalkyl, C₇-C₁₂bicycloalkyl, C₂-C₁₁heterocycloalkyl,carbocyclic C₆-C₁₆aryl, C₂-C₁₅heteroaryl, carbocyclic C₇-C₁₆aralkyl andC₂-C₁₅heteroarylalkyl, which may in turn be substituted by theabovementioned functional groups and interrupted by divalent radicals.

Examples of C₁-C₂₀alkyl are methyl, ethyl, n-propyl or isopropyl and n-,sec- or tert-butyl and also straight-chain or branched pentyl, hexyl,heptyl, octyl, isooctyl, nonyl, tert-nonyl, decyl, undecyl or dodecyl.

Examples of C₄-C₁₂cycloalkyl are cyclopropyl, dimethylcyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

Examples of C₇-C₁₂bicycloalkyl are bornyl and norbornyl.

C₂-C₁₁heterocycloalkyl preferably contains 4 or 5 carbon atoms and oneor two heteroatoms selected from the group consisting of O, S and N.Examples are the substituents derived from oxirane, azirine,1,2-oxathiolane, pyrazoline, pyrrolidine, piperidine, piperazine,morpholine, tetrahydrofuran or tetrahydrothiophene.

Carbocyclic C₆-C₁₆aryl is, for example, monocyclic, bicyclic ortricyclic, e.g. phenyl, naphthyl, indenyl, azulenyl or anthryl.

C₁-C₁₅heteroaryl is preferably monocyclic or fused to a furtherheterocycle or an aryl radical, e.g. phenyl, and preferably contains oneor two, in the case of nitrogen up to four, heteroatoms selected fromthe group consisting of O, S and N. Suitable substituents are derivedfrom furan, thiophene, pyrrole, pyridine, bipyridine, picoline, γ-pyran,γ-thiopyran, phenanthroline, pyrimidine, bipyrimidine, pyrazine, indole,cumarone, thionaphthene, carbazole, dibenzofuran, dibenzothiophene,pyrazole, imidazole, benzimidazole, oxazole, thiazole, dithiazole,isoxazole, isothiazole, quinoline, isoquinoline, acridine, chromene,phenazine, phenoxazine, phenothiazine, triazine, thianthrene, purine ortetrazole.

Carbocyclic C₇-C₁₆aralkyl preferably contains from 7 to 12 carbon atoms,e.g. benzyl, 1- or 2-phenethyl or cinnamyl.

C₂-C₁₅heteroarylalkyl preferably consists of the abovementionedheterocycles substituting, for example, C₁-C₄alkyl radicals, dependingon the length of the carbon chain preferably at the end, but also in theadjacent position (1 position) or in the α position (2 position).

In a preferred embodiment, a cis enantiomer pair of the compound of theformula:

in which R₁ is C₁-C₄alkyl and R₂ is aryl, is prepared.

In process variant a), a cyclohexylidenamine, or the imine or nitrone(II), in particular the imine or nitrone of the formula:

in which R₁ and R₂ are as defined above and which can be in the syn oranti form, is hydrogenated in the presence of a copper-containingcatalyst and in the presence of a protic solvent.

In process variant b), a ketone (III), in particular a ketone of theformula

in which R₂ is as defined above, is reacted with a compound whichintroduces the group R₁—N→(O)_(n), in particular a primary amine,preferably methylamine, or an R₁-substituted hydroxylamine, inparticular N-methylhydroxylamine, and the imine (II) obtainable as anintermediate is hydrogenated in-situ in the presence of acopper-containing catalyst and in the presence of a protic solvent.Instead of a racemic compound (II′) or (III′), it is also possible touse an optically pure compound (II′) or (III′) and convert this into acis compound (I′).

The invention preferably provides a process for preparing the ciscompound (I′) in which R₁ is methyl and R₂ is 3,4-dichlorophenyl, whichcomprises

a) hydrogenating an imine or nitrone (II′) in which R₁ is methyl and R₂is 3,4-dichlorophenyl in the presence of a copper-containing catalystand in the presence of a protic solvent or

b) reacting a ketone (III′) in which R₂ is 3,4-dichlorophenyl withmethylamine or N-methylhydroxylamine, hydrogenating the imine or nitrone(II) obtainable as an intermediate in the presence of acopper-containing catalyst and in the presence of a protic solvent andisolating the cis compound (I′).

Suitable catalysts for the hydrogenation reaction in variants a) and b)are copper-containing catalysts, e.g. skeletal copper catalysts,supported copper catalysts, copper chromite catalysts, copper-zinc oxidecatalysts, copper boride catalysts or Urushibara copper catalysts.

In a preferred embodiment of the process, further elements in additionto copper are present in the catalyst. Examples are aluminium, chromium,zinc, barium, manganese, zirconium, vanadium, molybdenum, titanium,tantalum, niobium, tungsten, nickel, cobalt, bismuth, tin, antimony,hafnium, rhenium, iron, cadmium, lead and germanium and mixturesthereof. The amount of the element added can vary within wide limits. Itcan be in the range from 10 ppm to 200%, based on the amount of copperused. Particularly suitable elements are aluminium, zinc, chromium,barium and manganese. The elements can, for example, be present in theform of oxides or salts such as chromates.

Raney copper is an example of a suitable skeletal copper catalyst.

Examples of supports are carbon, aluminium oxide, silicon dioxide,Cr₂O₃, zirconium dioxide, zinc oxide, calcium oxide, magnesium oxide,barium sulfate, calcium carbonate and aluminium phosphate. The coppercan be present in an amount of about 1.0-20.0% by weight bound to thesupport.

A suitable copper chromite catalyst has the empirical formulaCuO.CuCr₂O₄. CuCr₂O₄ is known, cf. C.A.R.N. 12018-10-9 and GmelinsHandbuch der Anorganischen Chemie, 8^(th) edition, Volume Copper, PartB, Issue 3, System number 60, page 60. Another customary designation iscopper(II) chromate(III). Copper chromite catalysts having varyingproportions of CuO and CuCr₂O₄, Raney copper catalysts andcopper-zinc-aluminium oxide catalysts are commercially available in pureform or in a form doped with the abovementioned elements.

In a preferred embodiment of the process, the copper-containingcatalysts used are copper chromite catalysts or catalysts comprisingcopper, zinc, barium and aluminium in the form of oxides.

The catalysts mentioned are present in the reaction mixture in an amountof from about 0.1 to 100% by weight, in particular 1-20% by weight,based on the amount of starting material used.

The copper-containing catalysts can be used in the process in variousways:

-   -   in the form of ready-to-use catalysts;    -   in the form of prehydrogenated catalysts or    -   in the form of catalysts prepared in situ from suitable        precursors, e.g. copper salts or oxides, and further compounds.

The prehydrogenation can, for example, be carried out by treating asuspension of the catalyst in a suitable solvent under from 5 to 150 barof hydrogen at 80-250° C. for from half an hour to 5 hours, or bypassing hydrogen over the dry catalyst at from atmospheric pressure to50 bar at from 100 to 500° C.

In a preferred embodiment of the process, the catalyst used is activatedby hydrogenation in the solvent which is used for the hydrogenation ofthe imine or nitrone (“prehydrogenation”). After the hydrogenation, thecatalyst can be separated off, for example, by filtration when theprocess is carried out batchwise.

Imines (II) can be prepared by reaction of ketones (II) with a compoundwhich introduces the group R₁—N, in particular a primary amine,preferably methylamine. The preparation of imines (II) is carried out bya method analogous to that described in U.S. Pat. No. 4,536,518.

Nitrones (II) can be prepared by reaction of ketones (II) with acompound which introduces the group R₁—N→O, e.g. R₁-substitutedhydroxylamine, in particular N-methylhydroxylamine. The preparation ofnitrones (II) is carried out by a method analogous to that described inWO 98/27050.

The hydrogenation is carried out in the presence of a protic organicsolvent. Suitable protic solvents are, for example, monohydric andpolyhydric alcohols, preferably C₁-C₅monoalcohols such as isopropanol,n-butanol, methanol or very particularly preferably ethanol. Mixtures ofvarious protic solvents can also be used.

In variant b), acidic auxiliaries, e.g. organic monobasic or polybasicacids having more than two carbon atoms, e.g. acetic acid, propionicacid or malonic acid, mineral acids such as sulfuric acid, Lewis acids,e.g. boron trifluoride, or solid acids such as zeolites or Nafion®and/or desiccants such as sodium sulfate may be added if desired.

In variant b), an excess of up to 50 mol of the amine used, e.g.methylamine in the form of methylamine gas or as a solution, e.g. inethanol, is added.

In both variants, the process can advantageously be carried out in theliquid phase, either batchwise or continuously, in particular using acatalyst suspension as a liquid-phase hydrogenation or in a bubblecolumn or using a shaped catalyst in a trickle bed. The reaction canalso be carried out in the gas phase using a pulverulent catalyst in afluidized bed or using a shaped catalyst in a fixed bed.

The hydrogenation can be carried out within a wide temperature range.Temperatures of from 60° C. to about 250° C., in particular from 90° to150° C., have been found to be advantageous.

The hydrogen pressure in the hydrogenation can vary within wide limits,e.g. 1-100 bar, preferably 5-50 bar, in particular 10-20 bar. Thehydrogen pressure employed depends essentially on the hydrogenationfacility available. In place of molecular hydrogen, it is also possibleto use a hydrogen donor such as isopropanol at relatively hightemperatures of about 100° C.

The reaction time can vary within wide limits. It depends on thecatalyst used, on the hydrogen pressure, on the reaction temperature andon the hydrogenation facility used. It can be, for example, from half anhour to 24 hours. Reaction times of from about half an hour to two hoursare advantageous.

The isolation of the reaction products is carried out by known methodsand is described in the examples. Removal of the catalyst and thesolvent can be followed by the customary separation methods, e.g.preparative thin layer chromatography, preparative HPLC, preparative gaschromatography, etc. The cis racemate obtained from racemiccyclohexylidenamine can, without further purification, be resolved intothe optically pure enantiomers by means of the known methods ofseparating enantiomers, e.g. by means of preparative chromatography overchiral supports (HPLC) or by precipitation or crystallization usingoptically pure precipitants, e.g. using D-(+)- or L-(−)-mandelic acid or(+)- or (−)-10-camphorsulfonic acid. When enantiomerically pure4-substituted cyclohexylidenamine is used as starting material, thehydrogenation process of the invention gives the enantiomerically pure4-substituted cyclohexylamine directly.

The invention likewise provides for the use of copper-containingcatalysts for the diastereoselective hydrogenation ofcyclohexylidenamines. Preference is given to using copper chromitecatalysts, CuCrBa oxide or CuZnAl oxide catalysts for thediastereoselective hydrogenation of cyclohexylidenamines.

The following examples illustrate the invention:

EXAMPLE 1

The prehydrogenated catalyst (CuCrBa oxide, 2% based on imine startingmaterial) is placed in an autoclave, 15 g of4-(3,4-dichlorophenyl)-1-methylimino-1,2,3,4-tetrahydronaphthalene areadded and the mixture is covered with 30 ml of ethanol.

The autoclave is closed and the air is replaced by nitrogen. Thenitrogen is subsequently replaced by hydrogen and an initial pressure of12 bar of hydrogen is set and the stirrer is switched on. The autoclaveis then heated to 130° C. and commencement of the reaction can beobserved above 90° C. After a temperature of 130° C. has been reached,the reaction takes about 45 minutes-1 hour until hydrogen absorptionceases. The hydrogenation time is 20 minutes. The autoclave issubsequently cooled, the catalyst is filtered off and the solution isevaporated on a rotary evaporator.

The cis/trans ratio of the4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamineobtained is determined by means of HPLC: 99.6:0.4.

Yield: 86% of the theoretical yield of pure cis racemate

EXAMPLE 2

The procedure described in Example 1 is repeated, except that thehydrogenation is carried out at 150° C. (instead of 130° C.). Thehydrogenation time is still about 20 minutes.

Cis/trans ratio of the4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamineobtained: 98.8:1.2

Yield: 83% of the theoretical yield of pure cis racemate.

EXAMPLE 3

The procedure described in Example 1 is repeated, except that thecatalyst concentration is 7%, based on the imine.

Cis/trans ratio of the4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamineobtained: 97:3.

Yield: 85% of the theoretical yield of pure cis racemate.

EXAMPLES 4 to 6

The procedure described in Example 1 is repeated, except that the 30 mlof ethanol is replaced by an equal amount of methanol, isopropanol orn-butanol.

1. A process for preparing compounds of the formula

in which R₁ and R₂ are, independently of one another, hydrocarbonradicals and A are substituents and m is an integer from 0 to 4 whichdefines the number of substituents A, which comprises a) hydrogenating acyclohexylidenamine of the formula:

in which n is zero or 1, R_(1,) R_(2,) A and m are as defined above, inthe presence of a copper-containing catalyst and in the presence of aprotic solvent; or b) reacting a ketone of the formula:

in which R_(2,) A and m are as defined above, with a compound whichintroduces the group R₁—N→(O)_(n), hydrogenating the imine or nitrone(II) obtainable as an intermediate in the presence of acopper-containing catalyst and in the presence of a protic solvent andisolating the cis compound (I).
 2. A process for preparing compounds ofthe formula I according to claim 1 in which the hydrocarbon radicals R₁or R₂ are selected from the group consisting of C₁-C₂₀alkyl,C₄-C₁₂cycloalkyl, C₄-C₁₂cycloalkenyl, C₂-C₁₁heterocycloalkyl,carbocyclic C₆-C₁₆aryl, C₂-C₁₅heteroaryl, carbocyclic C₇-C₁₆aralkyl andC₂-C₁₅heteroarylalkyl and are substituted by functional groups from thegroup consisting of amino, C₁-C₄alkylamino, C₁-C₄dialkylamino, hydroxy,carboxy and halogen, m is two and A are substituents R₃ and R₄ which areindependently or together saturated aliphatic, cycloaliphatic orheterocycloaliphatic radicals or carbocyclic, heterocyclic orcarbocyclic-heterocyclic radicals which may be combined in any way withfurther radicals of this type or be substituted by functional groupsfrom the group consisting of amino, C₁-C₄alkylamino, C₁-C₄dialkylamino,hydroxy, carboxy and halogen, which comprises a) carrying out theprocess variant a) using a correspondingly substituted imine (II) inwhich m is 2 and R_(1,) R_(2,) R₃ and R₄ are as defined above, or b)carrying out the process variant b) using a correspondingly substitutedketone (III) in which m is 2 and R₃ and R₄ are as defined above.
 3. Aprocess according to claim 1 for preparing the cis enantiomer pair ofthe compound of the formula

in which R₁ is C₁-C₄alkyl and R₂ is aryl, wherein a) an imine or nitroneof the formula

in which R₁ is methyl and R₂ is 3,4-dichlorophenyl, is hydrogenated inthe presence of a copper-containing catalyst and in the presence of aprotic solvent; or a ketone of the formula

in which R₂ is as defined above, is reacted with a compound whichintroduces the group R₁—N, the imine or nitrone (II) obtainable as anintermediate is hydrogenated in situ in the presence of acopper-containing catalyst and in the presence of a protic solvent andthe compound (I′) is isolated.
 4. A process according to claim 3 forpreparing the cis compound (I′) in which R₁ is methyl and R₂ is3,4-dichiorophenyl, wherein a) an imine or nitrone (II′) in which R₁ ismethyl and R₂ is 3,4-dichlorophenyl is hydrogenated in the presence of acopper-containing catalyst and in the presence of a protic solvent or b)a ketone (III′) in which R₂ is 3,4-dichlorophenyl is reacted withmethylamine or N-methylhydroxylamine, the imine or nitrone (II)obtainable as an intermediate is hydrogenated in the presence of acopper-containing catalyst and in the presence of a protic solvent andthe cis compound (I′) is isolated.
 5. A process according to claim 1,wherein the compound (I) is prepared by hydrogenation in the presence ofa copper chromite, CuCrBa oxide or CuZnAl oxide catalyst.
 6. A processaccording to claim 1, wherein the protic solvent used is a monohydric orpolyhydric alcohol.
 7. A process according to claim 6, wherein theprotic solvent used is a C₁-C₅monoalcohol.